Zhao X M, Hauache O, Goldsmith P K, Collins R, Spiegel A M
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
FEBS Lett. 1999 Apr 1;448(1):180-4. doi: 10.1016/s0014-5793(99)00368-3.
A missense mutation, A843E, in the seventh transmembrane domain of the human Ca2+ receptor, identified in a subject with autosomal dominant hypocalcemia, was found to cause a constitutive activation while at the same time lowering the maximal response of the receptor to Ca2+. A truncated human Ca2+ receptor lacking the majority of the N-terminal extracellular domain failed to respond to Ca2+ despite an excellent cell surface expression. The A843E mutant version of this truncated receptor showed constitutive activation. These results identify A843 as a critical residue for maintaining the inactive conformation of the human Ca2+ receptor. Substitution of glutamate, but not lysine or valine, for alanine 843 leads to activation of the human Ca2+ receptor in a manner that no longer depends upon Ca2+ binding to the extracellular domain.
在一名常染色体显性遗传性低钙血症患者中发现，人类钙离子受体第七跨膜结构域存在错义突变A843E，该突变导致受体组成性激活，同时降低了受体对钙离子的最大反应。一个缺少大部分N端胞外结构域的截短型人类钙离子受体，尽管在细胞表面有良好表达，但对钙离子无反应。这种截短型受体的A843E突变体表现出组成性激活。这些结果表明，A843是维持人类钙离子受体无活性构象的关键残基。用谷氨酸取代843位的丙氨酸可导致人类钙离子受体激活，且这种激活不再依赖于钙离子与胞外结构域的结合，而用赖氨酸或缬氨酸取代则不会。
